Method of treatment of glutathione deficient mammals

ABSTRACT

Glutathione (GSH) is a tripeptide of extreme importance as a catalyst, reductan, and reactant. It can be depleted intracellulary either by forming a direct complex with an electrophilic agent (accomplished investigationally by agents such as bromobenzene or diethyl maleate), by way of inhibition of synthesis, or by subjecting cells to oxidant stress. Most cells, except for epithelia cells, do not have a direct transport capacity for intact GSH. Non-epithelial cells must either transport precursor substrates for GSH synthesis or salvage amino acids from circulating GSH for reuse in intracellular resynthesis. Dietary cysteine is a rate limiting substrate for the synthesis of glutathione and also inhibits GSH efflux. Although GSH is synthesized from precursors in virtually all cells, the liver is the main source of plasma GSH. Protection and support of liver function is paramount to elevating GSH levels. The disclosure is also of a unique combination of nutritional supplements including n-acetyl cysteine, vitamin C, l-glucosamine, n-acetyl d-glucosamine, quercitin, sylimarin, Alpha lipoic acid and high protein, low fat whey that are combined to support various bodily systems involved in glutathione synthesis, reutilization and storage; all intended to elevate glutathione concentration in the mammalian cell.

This application is a Continuation of Ser. No. 09/994,164, filed Nov.26, 2001, now RE 39,705, which is a Reissue of Ser. No. 09/302,217,filed Apr. 29, 1999, now U.S. Pat. No. 6,262,019, which claims thebenefit of Provisional Application No. 60/083,661 filed Apr. 30, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention provides a method of improving glutathione (GSH)concentrations, both intra and extra-cellularly, in mammals, therebyimproving the cellular and humoral immune response. It comprises oraladministration of a therapeutically effective amount of nutritionalsupplement which is composed of critical and synergistic quantities ofamino acids, peptides, and bioflavanoids.

2. Brief Description of Related Art

Glutathione is a well-known tripeptide, which exists in two basic forms.The antioxidant form or “reduced glutathione” tripeptide isconventionally called “glutathione” and abbreviated as “GSH”. Theoxidized form is a sulfur-sulfur linked compound known as glutathionedisulfide (GSSG).

Glutathione in its biologically active, reduced form (GSH) has theformula:

and is appropriately named γ-L-Glutamyl-L-cysteinylglycine. It isubiquitous in animals, plants, and microorganisms and being watersoluble is found mainly in the cell cytosol and other aqueous phases ofthe living system. Glutathione often attains millimolar levels insideliving cells, which makes it one of the most highly concentratedintracellular antioxidants.

Glutathione is homeostatically controlled, both inside the animal celland outside. Enzyme systems synthesize it, utilize it, and regenerate itper the gamma-glutamyl cycle. (Meister A. Glutathione, Ascorbate andCellular Protection Cancer Res (Suppl) 1994 (Apr 1); 54:1969S-1975S).

Glutathione is most concentrated in the mammal liver (10 mM), where theP450 Phase II” enzymes require it to convert fat-soluble substances intowater-soluble GSH conjugates in order to facilitate their excretion.While providing GSH for their specific needs, the liver parenchymalcells export GSH to the outside, where it serves as systemic sourceof-SH/reducing power.

Briefly, glutathione synthesis occurs within animal cells in two closelylinked enzymatically controlled reactions that utilize AdenosineTriphosphate (ATP) and draw on nonessential amino acids as substrates.First, cysteine and glutamate are combined (by the enzyme gamma-glutamylcysteinyl synthetase, with availability of cysteine usually being therate-limiting factor. Cysteine is generated from the essential aminoacid methionine, from the degradation of dietary protein, of fromturnover of endogenous proteins. The buildup of GSH acts tofeedback-inhibit this enzyme, thereby helping to ensure homeostaticcontrol over GSH synthesis.

The second GSH synthesis reaction combines gamma-glutamylcysteine withglycine to generate GSH (catalyzed by GSH synthetase).

With regard to the essentiality of GSH for the survival of the mammal,substantial information is available from studies on hereditary GSHdepletion in the human, and from experimental depletion and repletion ofGSH in animal models and cell cultures, see for example: Meister A.Larsson A. Glutathione Synthetase Deficiency and Other Disorders of theGamma-Glutamyl Cycle; Scriver CR. et al eds. The Metabolic and MolecularBases of Inherited Disease (Volume I). New York: McGraw-Hill:1995:1461-1495 (Chapter 43); and Beutler E. Nutritional and MetabolicAspects of Glutathione, Annu Rev Nutr 1989;9:287-302.

Reduced GSH levels in mammalian cells are associated with a wide varietyof pathophysiologic states, including hepatic dysfunction, malignancies,HIV infection, pulmonary disease, Parkinson's disease, relatedimmunologic illnesses and physiological conditions; see for example thedescriptions in Kidd, Alternative Medicine Review, Vol. 2, No. 3, pages156-176 (1997).

The consequences of sustained GSH depletion are fatal. As cellular GSHis depleted, first individual cells die in those areas most affected.Then zones of tissue damage begin to appear. Localized free-radicaldamage spreads across the tissue in an ever-widening, self-propagatingwave.

An object of this invention is to promote gastrointestinal absorptionand intracellular uptake of components which will maximize intracellularreduced glutathione production by a mammal including a human.

SUMMARY OF THE INVENTION

The invention comprises a composition of matter, which comprises inadmixture:

N-acetylcysteine;

vitamin C; and

a pharmaceutically acceptable systemic carrier for oral administration.

In preferred embodiments, the invention further comprises one or more ofthe following:

alpha-lipoic acid;

sylmarin;

quercitin;

l-glutamine;

N-acetyl-d-glucosamine;

a probiotic.

The invention also comprises systemic administration of the compositionof the invention to a mammal suffering from low glutathione levels, tostimulate the natural production of glutathione in the biological cellsof the mammal.

The term “low glutathione levels” as used herein means a bloodglutathione level below about 440 μg glutathione/10¹⁰ erythrocytes,determined by the colorimetric method of Beutler et al., Improved Methodfor the Determination of Blood Glutathione, J. Lab. Clin. Med.,61;882-8(1963). Normal levels in humans ranges from about 440 to 654μg/10¹⁰erythrocytes.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

Recently, there have been many scientific papers published discussingthe direct relationship between decreased glutathione levels and theprogression of many chronic diseases. Glutathione functions as anantioxidant, antitoxin and protector of red blood cells, and isextremely important to the immune system. It neutralizes free radicalsminimizing the damage they cause and is profoundly important forcellular homeostasis.

As with other cell types, the proliferation, growth, and differentiationof immune cells is dependent on GSH. Both the T and the B lymphocytesrequire adequate levels of intracellular GSH to differentiate, andhealthy humans with relatively low lymphocyte GSH were found to havesignificantly lower CD4 counts; Kinscherf R. Fischbach T. Mihm S. et al.Effect of glutathione depletion and oral N-acetylcysteine treatment onCD4+ and CD8+ cells. FASEB J 1994;8:448-451. Intracellular GSH is alsorequired for the T-cell proliferative response to mitogenic stimulation,for the activation of cytotoxic T “killer” cells, and for many specificT-cell functions, including DNA synthesis for cell replication, as wellas for the metabolism of interleukin-2 which is important for themitogenic response; Wu D. Meydani S N, Sastre J. et al. In-vitroglutathione supplementation enhances interleukin-2 production andmitogenic response of peripheral blood mono-nuclear cells from young andold subjects; J Nutr 1994;124:655-663.

In summary, it has been demonstrated that decreased levels ofglutathione may be a result of various types of prolonged stress,increased free radical formation and hyperactivity of the immune system.These factors in turn compromise the health of mammalian cells. Despitethe apparent importance of adequate glutathione levels, little emphasishas heretofore been placed on replacing depleted stores. Someglutathione comes from the diet but the majority is made in the liver.

Studies have demonstrated that oral GSH supplementation is not wellabsorbed by many of the mammal's cells and does not replenish lossesinside cells where it is most needed; Witschi A. Reddy S. Stofer B. etal. The systemic availability of Oral Glutathione. Eur. J Clin.Pharmacol. 1992;43:667-669.

The sulfur-containing amino acid l-cysteine is the precursor that mostlimits the cellular biosynthesis of GSH. When substituted into the dietin place of the total protein allowance it was effective in raising GSHlevels (see Witschi et al., supra.)

Glutathione esters, synthetic compounds prepared by linking the glycolend of GSH into ester bonds, have been the subject of much research byMeister, Anderson, supra., as potential oral GSH delivery compounds (seealso U.S. Pat. No. 4,784,685). These esters do appear to be effectiveGSH delivery vehicles, but have the disadvantage that they yieldalcohols in vivo when their ester bonds are broken, and their safetyover the long term has yet to be satisfactorily demonstrated.

We have discovered that to efficiently raise the level of glutathioneintracellularly, it is necessary to employ several different mechanismsthat work simultaneously. First, essential elements needed by the bodyfor the manufacture of glutathione must be introduced. Second,gastro-intestinal health of the mammal must be optimal to facilitatenutrient absorption. Third, the liver function must be supported andprotected as the liver is the glutathione “manufacturing and storagehouse”. Lastly, recycling existing glutathione and enhancing enzymaticreactions that promote glutathione synthesis are also importantfunctions which are advantageous to support.

The essential element needed by the mammalian cell to manufactureglutathione (GSH) is N-acetylcysteine (NAC). It has proven to be themost efficient dietary source of glutathione precursor. It is aprecursor and the main limiting factor necessary for the body tomanufacture reduced glutathione. NAC is well absorbed by the intestineand readily converted by the mammalian cell (particularly in the liver)to glutathione.

The absorption of N-acetylcysteine (NAC) and transport across thecellular membrane is facilitated by the presence of ascorbic acid(vitamin C). Vitamin C maximizes NAC transport across biological cellmembranes and helps to conserve existing glutathione stores within thecell cytosol.

The utilization of N-acetylcysteine within the biological cell tosynthesize glutathione is improved by the presence of alpha lipoic acid.Alpha lipoic acid increases the cell's ability to make glutathione. Itenables the key enzyme required to glutathione synthesis to work underoptimum conditions and induces a substantial increase in intracellularreduced glutathione; see Busse E. Zimmer G. Schopohl B, et al. Influenceof alpha-lipoic acid on intracellular glutathione in vitro and in vivo;Arzneimittel-Forschung 1992;42:829-831; and Han D. Handelman G.Marcocci, et al. Lipoic Acid Increases de novo Synthesis of CellularGlutathione by Improving Cystine Utilization, Biofactors 1997;6:321-338.1995:29: 1263-73.

As mentioned above, support of liver function in the mammal beingtreated for low glutathione levels is advantageous. For this purpose,there may be orally administered to the mammal the following:

A. Sylimarin serves to improve and restore liver function. It quenchesfree radicals, reduces potential toxicity, and stimulates proteinsynthesis necessary to create new liver cells. Also known as “silibin”,“silybin” or “silybinin”, Silymarin is a generic term for extract fromthe mature fruits of Silybum marianum (sometimes Carduus marianus),commonly known as milk thistle; see Madaus AG publication: Legalon.Koln, Germany, 1989 and Valenzuela A, et al. Silymarin ProtectionAgainst Hepatic Lipin Peroxidation Induced by Acute Ethanol Intoxicationin Rats, Biochemical Pharmacology, 1985:34(12):2209-2212. Sylimarin isavailable under the trade name Legalon®, from Madaus AG, (JarrowFormulas, Inc.; Madaus, 1989).

B. Quercetin[2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one] is usedfor its ability to eliminate toxic compounds found in the liver. It hasanti-hepatotoxic, antiviral, anti-inflammatory and antibacterialproperties. It may be synthesized by the method of Shakhova et al., Zh.Obsheh. Khim., 32, 390 (1962).

Advantageously, the following nutritionals are also employed in themethod of the invention.

L-glutamine is an essential dietary component for the support ofgastrointestinal growth and function and it is utilized as fuel in thesmall intestines. It is used by the intestinal tract in large amountsfor energy during periods of physiological stress. It has been shown toperserve liver glutathione after lethal hepatic injury and nourishtissues in the GI tract, liver and immune system, see for example;Souba, W.W., et al. The Role of Glutamine in Maintaining a Healthy Gutand Supporting the Metabolic Response to Injury and Injection. J. OfSurgical Res., 990:48(4):83-91.

N-acetyl-d-glucosamine (NAG) is a key precursor in the biosynthesis ofmucosal glycoproteins that form glycocalyx. The glycalyx is the mostsuperficial, highly viscous layer of the gut mucosa that comes incontact with intestinal contents. The glycoprotein layer acts to protectthe underlying tissues from exposure to enzymes, acid and bacterialassault while providing a selectively absorptive surface, Wilmore, D.W., et al, The gut: a Central Organ After Surgical Stress; Surgery 1988:104, (5):917-23.

Probiotics or “healthy bacteria” are necessary as they breakdownnutrients, eliminate toxins and inhibit harmful bacteria that entermammalian systems through the GI tract. The term “Probiotic” is definedherein as “A live microbial food supplement which beneficially affectsthe host mammal by improving its microbial balance”. Representative ofhealthy bacteria are isolates of bifidobacteria, lactobacilli, such asLactobacillus acidophilus and Lactobacillus casei, propionibacteria, andenterococci. Lactobacilli are preferred in the composition and method ofthe invention (see Perdigon, G. et al., Immunology 63:17-23 (1988)).More preferably Lactobacillus rhamnosus, Lactobacillus casei,Bifidobacterium longum, Bifidobacterium infantis, Lactobacillusacidophillus, and Saccharomyces boulardi are used.

Finally, a source of dietary protein is preferred and advantageous tosupplement the nutritional needs of the mammal. We have found that thecompositions of the invention and the method herein described areoptimized by inclusion of a biologically active whey protein compositioncomprising an undenatured whey protein concentrate obtained from rawmammalian milk. This concentrate contains substantially all of the heatlabile whey protein found in the raw milk. Representative of concentratewhich are commercially available include Promod™, available from RossLaboratories, Division of Abbott Laboratories, Chicago, Ill.Concentrates may also be prepared by the method described in U.S. Pat.No. 5,290,571, incorporated herein by reference thereto. The undenaturedwhey protein concentrates also contain a rich variety of immunoglobulinswhich boast the immunologic response of the mammal treated with theconcentrates; see for example U.S. Pat. No. 5,456,924 which isincorporated herein by reference thereto.

A high protein, low fat whey has immuno-supportive properties. It isrich in naturally active immunoglobulins, essential amino acids andother important nutrients critical for proper nutrient utilizationwithin the gut.

We have discovered that the ingredients described above worksynergistically to provide the necessary nutrients required forglutathione production while supporting the mammal's ability to produceand preserve existing stores of GSH. The effect of the admixture ofingredients is far more significant than the individual ingredientsalone.

This invention also relates also to pharmaceutical dosage unit forms forsystemic administration (oral, topical administration) which are usefulin treating mammals, including humans. The term “dosage unit form” asused in this specification and in the claims refers to physicallydiscrete units suitable as unitary dosage for mammalian subjects, eachunit containing a predetermined quantity of the essential activeingredient; calculated to produce the desired effect in combination withthe required pharmaceutical means which adapt said ingredient forsystemic administration. Examples of dosage unit forms in accordancewith this invention are tablets, capsules, orally administered liquidpreparations in liquid vehicles, suppositories, and dry preparations forthe extemporaneous preparation of preparations in a liquid vehicle.Solid diluents or carriers for the solid oral pharmaceutical dosage unitforms are selected from the group consisting of lipids, carbohydrates,proteins and mineral solids, for example, starch, sucrose, kaolin,dicalcium phosphate, gelatin, acacia, corn syrup, corn starch, talc andthe like. Capsules, both hard and soft, are formulated with conventionaldiluents and excipients, for example, edible oils, talc, calciumcarbonate, calcium stearate, magnesium stearate and the like. Liquidpharmaceutical preparations for oral administration may be prepared inwater or aqueous solutions which advantageously contain suspendingagents, such as for example, sodium carboxymethylcellulose,methylcellulose, acacia, polyvinyl pyrrolidone, polyvinyl alcohol andthe like.

Such preparations must be stable under the conditions of manufacture andstorage, and ordinarily contain in addition to the basic solvent orsuspending liquid, preservatives in the nature of bactericidal andfungicidal agents, for example, parabens, chlorobutanol, benzyl alcohol,phenol, thimerosal, and the like. In many cases it is preferable toinclude isotonic agents, for example, sugars or sodium chloride.Carriers and vehicles include vegetable oils, water, ethanol, andpolyols, for example, glycerol, propylene glycol, liquid polyethyleneglycol, and the like.

The pharmaceutical dosage unit forms are prepared in accordance with thepreceding general description to provide an effective amount of theessential active ingredient per dosage unit form in admixture with themeans for adaptation to systemic administration. In general, the unitdose form will contain 3 to 73 percent by weight of the essential activeingredient.

It will be appreciated that the exact dosage of the essential activeingredient constituting an effective amount for treatment of a mammalaccording to the method of the invention will vary greatly depending onthe specific nature of the clinical condition being treated, severity ofthe condition, species of mammal, age, weight and condition of themammal, mode of administration of the dosage form and the specificformulation being administered. The exact dose required for a givensituation may be determined by administration of a trial dose andobservation of the clinical response. In general, an effective amount tobe administered will be within a range of from about 0.1 mg. per kg. toabout 50 mg. per kg. of body weight of the recipient, daily. Preferably0.5 mg./kg. to about 25 mg./kg. daily is provided. In most instances, asingle month of administration will effect a noticeable response andbring about the result desired. In cases such as the treatment ofimmunological conditions however, it may be desirable to repeat theadministrations several times daily over longer periods of time.

The following examples and preparations describe the manner and processof making and using the invention and set forth the best modecontemplated by the inventor of carrying out the invention but are notto be construed as limiting.

EXAMPLE 1

A mixture of the following ingredients is prepared by hand mixing:

Ingredient Quantity N-acetylcysteine 1,000 to 20,000 mg vitamin C 5,000to 50,000 mg alpha-lipoic acid 100 to 2,500 mg sylmarin 100 to 2,500 mgQuercetin 100 to 2,500 mg l-glutamine 500 to 2,000 mgN-acetyl-d-glucosamine 500 to 2,000 mg whey protein concentrate 1,000 to20,000 mg Lactobacillus acidophilus Twenty Million to One Billion CFU;Schiff Products, Inc., Salt Lake City, Utah. orange essence flavorAdjust to taste

The mixture which constitutes the essential active ingredient of apreferred embodiment of the invention, together with a flavorant may becompounded into wafers, tablets or capsules containing 750 to 14,000 mgof active ingredient. In an uncompounded form, the powder dry mixturemay be orally administered to a human (one teaspoonful, once or twicedaily) as a dietary supplement or as recommended by a health careprofessional. Alternatively, the dry powder may be mixed with juice,water or food to facilitate administration.

EXAMPLE 2

Three dosage units in powder form, each containing 500 mg of essentialactive ingredient (e.g an amount of the mixture of Example 1, supra.were prepared from the following ingredients:

essential active ingredient 1500 g starch (Rx-1500) 300 g magnesiumstearate, USP 39 g colloidal silicic acid 19.5 g Avicel ® pH 102. q.s.to 3900 g

The essential active ingredient was ground through a 0.25 mm sieveopening screen. The powdered active ingredient, with 50% of the totalamount of magnesium stearate be used, colloidal silicic acid and Avicel®pH 10.2 were passed through a 40 mesh sieve, mixed for 20 minutes andthen slugged. The slugs were broken down by forcing through a screen No.11, and mixed with the remaining magnesium stearate.

One dosage given orally 1-4 times a day is useful in the relief ofimmuno-deficiency in adult humans provoked by infective disease, orother etiological causes.

EXAMPLE 3

Three thousand dosage units for oral use, each containing 750 mg of theessential active ingredient, were prepared from the followingingredients:

essential active ingredient 750 g colloidal silicic acid 30 g magnesiumstearate, USP 30 g microcrystalline cellulose 150 g lactose 90 g

In accordance with the active ingredient potency, the amount of lactosewas adjusted to achieve a weight of 900 mg for each dosage unit. Theingredients were passed through a 40 mesh sieve and mixed for 30minutes. The powder may be mixed into a drink or inserted into hardgelatin capsules No. 0 and filled using Zanazi, model RV-59 equipment.The capsules should be preserved in airtight, light-resistantcontainers.

When administered to a human adult suffering from low levels ofglutathione (GSH) 1 to 4 dosage units daily, the level is adjustedupward to a normal range.

EXAMPLE 4

A mixture of the following ingredients is formed into a powdered dosageform in the following proportion:

Ingredient Quantity Vitamin C (ascorbate) 1000 mg N-acetyle cysteine1500 mg L-Glutamine 3000 mg N-acetyle d-glucosamine 500 mg Alpha-Lipoicacid (ALA) 75 mg Quercetin 75 mg Sylimarine 100 mg Whey protein 500 mgConjugated linoteic acid (CLA) 500 mg Orange flavor 380 mg Rice syrup1516 mg Malic acid 7.8 mg Citric acid 7.8 mg Stevia 455 mg GI Balance(Probiotic) 300 mg

Our studies have shown that the administration of the above dosage unit(one rounded teaspoon) mixed into a liquid 1-4 times (preferably 2times) a day is useful in the relief of immuno-deficiency in adulthumans provoked by infective disease, or other etiological causes. Forexample, the inventive composition can be used effectively to improveheptatic function e.g. decreased inflamation (ALT) in patients withchronic hepatitis C and patients who are receiving protease inhibitorsas part of HAART therapy for HIV. Both groups demonstrated an increasein intra lymphocyte GSH levels after the administration of the inventivecomposition.

Our studies have shown systemic administration of the compositionresults in an improvement in T lymphocyte function which correlatesdirectly with an increased intra lymphocyte GSH. In addition, our datademonstrates that the inventive composition and method shifts the T-cellbalance from TH2 (allergy producing) to TH1 (viral/tumor killing) andthe increases intra lymphocyte GSH correlate directly with decreasedlevels of IgE the immunoglobulin associated with allergies. Furtherstudies have revealed the following:

Systemic administration of the composition increases natural killer cellfunction which is considered a primitive first line of cellular immunedefense.

Systemic administration of the composition decreases serum cholesteroland triglycerides of between 10 and 20% in patients with a variety ofhyperlipidemias and a decrease in myalgias associated with illness andexercise and improved muscle recovery after exercise.

Systemic administration of the composition decreases fatigue in patientssuffering from a variety of illnesses including but not limited tochronic viral infections, HIV, hepatitis C, chronic fatigue, immunodeficiency syndrome, immune deficiencies, cancer, B-cell malignancies,including lymphomas, chronic leukemia, myeloma Waldenstrom's and MGUS.This makes the composition function as both a pharmaceutical and atherapeutic substance for patients suffering from the debilitatingconditions.

Initial studies have shown that the systemic administration of theinventive composition also increases energy in people without illnesswho are exposed to increased stress.

As such, the combination formulated will improve hepatic function inconditions associated with chronic viral infections, as well as anycondition associated with increased hepatic work or stress.

Thus by the present invention its advantages will be realized andalthough preferred embodiments have been disclosed and described indetail herein, its scope should not be limited thereby rather its scopeshould be determined by that of the appended claims.

1. A composition of matter, which comprises in admixture;N-acetylcysteine; N-acetyl-d-glucosamine vitamin C whereby the amount ofvitamin C is in an amount of at least 1000 mg. or greater to facilitatethe absorption of N-acetylcysteine across the cellular membrane; and apharmaceutically acceptable carrier for oral administration.
 2. Thecomposition of claim 1 further comprising one or more of the followingsubstances from the group consisting of alpha-lipoic acid, sylmarin,quercitin, l-glutamine, a probiotic, and dietary protein.
 3. Thecomposition of claim 1 further comprising alpha-lipoic acid, sylmarin,quercitin, l-glutamine, and a probiotic.
 4. The composition of claim 3further comprising dietary protein.
 5. The composition of claim 1further comprising flavorants.
 6. The systematic administration of apharmaceutically effective amount of the composition according to claim1 to a mammal suffering from low glutathione levels, to stimulate thenatural production of glutathione in the biologically active cells ofthe mammal.
 7. The systemic administration of a pharmaceuticallyeffective amount of the composition according to claim 2 to a mammalsuffering from hepatitis, to stimulate the natural production ofglutathione in the biologically active cells of the mammal.
 8. Thesystemic administration of a pharmaceutically effective amount of thecomposition according to claim 2 to a mammal suffering from HIV, tostimulate the natural production of glutathione in the biologicallyactive cells of the mammal.
 9. The systemic administration of apharmaceutically effective amount of the composition according to claim2 to a mammal suffering from allergies, to stimulate the naturalproduction of glutathione in the biologically active cells of the mammaland to promote the shift of the T-cell balance from TH2 to TH1 anddecrease levels of IgE.
 10. The systemic administration of apharmaceutically effective amount of the composition according to claim2 to a mammal to decrease serum cholesterol and triglycerides.
 11. Thesystemic administration of a pharmaceutically effective amount of thecomposition according to claim 2 to a mammal suffering from one or moreof the following illnesses from the group consisting of chronic viralinfections: HIV, hepatitis C, chronic fatigue, immuno deficiencysyndrome, immune deficiencies, cancer, B-cell malignancies, includinglymphomas, chronic leukemia, myeloma Waldenstrom's and MGUS to improveimmune defense productions and thereby mitigate the progression of theillnesses to thereby limit fatigue.
 12. The systemic administration of apharmaceutically effective amount of the composition according to claim2 to a mammal to decrease fatigue.
 13. The systemic administration of apharmaceutically effective amount of the composition according to claim2 to a mammal to decrease the biologic effects of stress.
 14. Thesystemic administration of a pharmaceutically effective amount of thecomposition according to claim 2 to a mammal to increase energy andimprove physical performance.
 15. Administration according to claim 6wherein a pharmaceutically effective amount is 0.1 mg/kg to about 50mg/kg of body weight of the mammal, daily.
 16. Administration accordingto claim 6 wherein a pharmaceutically effective amount is 0.5 mg/kg toabout 25 mg/kg of body weight of the mammal daily.
 17. The systemicadministration of a pharmaceutically effective amount of the compositionaccording to claim 2 to a mammal suffering from low glutathione levels,to stimulate the natural production of glutathione in the biologicallyactive cells of the mammal.
 18. The systemic administration of apharmaceutically effective amount of the composition according to claim3 to a mammal suffering from low glutathione levels, to stimulate thenatural production of glutathione in the biologically active cells ofthe mammal.
 19. The systemic administration of a pharmaceuticallyeffective amount of the composition according to claim 1 to a mammalsuffering from low glutathione levels, to stimulate the naturalproduction of glutathione in the biologically active cells of the mammaland reduce symptoms of diseases caused by excess unneutralized freeradicals.
 20. The systemic administration of a pharmaceuticallyeffective amount of the composition according to claim 2 to a mammalsuffering from low glutathione levels, to stimulate the naturalproduction of glutathione in the biologically active cells of the mammaland reduce symptoms of diseases caused by excess unneutralized freeradicals.
 21. The systemic administration of a pharmaceuticallyeffective amount of the composition according to claim 3 to a mammalsuffering from low glutathione levels, to stimulate the naturalproduction of glutathione in the biologically active cells of the mammaland reduce symptoms of diseases caused by excess unneutralized freeradicals.
 22. The systemic administration of a pharmaceuticallyeffective amount of the composition according to claim 19, wherein thedisease is a member of the group consisting of pulmonary oxygentoxicity, adult respiratory distress syndrome, broncopulmonerydysplasia, sepis syndrome, Parkinson's disease, encephalitis,endotoxemia, anoxia induced neuronal damage, ischemic reperfusioninjury, inflammatory diseases, systemic lupus erythematosis, myocardialinfarction, stroke, traumatic hemorrhage, spinal cord trauma, Crohn'sdisease, rheumatoid arthritis, diabetes, cataract formation, uvetis,emphysema, gastric ulcers, oxygen toxicity, neoplasia, undesired cellapoptosis, radiation sickness.
 23. The systemic administration of apharmaceutically effective amount of the composition according to claim20, wherein the disease is a member of the group consisting of pulmonaryoxygen toxicity, adult respiratory distress syndrome, broncopulmonerydysplasia, sepis syndrome, Parkinson's disease, encephalitis,endotoxemia, anoxia induced neuronal damage, ischemic reperfusioninjury, inflammatory diseases, systemic lupus erythematosis, myocardialinfarction, stroke, traumatic hemorrhage, spinal cord trauma, Crohn'sdisease, rheumatoid arthritis, diabetes, cataract formation, uvetis,emphysema, gastric ulcers, oxygen toxicity, neoplasia, undesired cellapoptosis, radiation sickness.
 24. The systemic administration of apharmaceutically effective amount of the composition according to claim21, wherein the disease is a member of the group consisting of pulmonaryoxygen toxicity, adult respiratory distress syndrome, broncopulmonerydysplasia, sepis syndrome, Parkinson's disease, encephalitis,endotoxemia, anoxia induced neuronal damage, ischemic reperfusioninjury, inflammatory diseases, systemic lupus erythematosis, myocardialinfarction, stroke, traumatic hemorrhage, spinal cord trauma, Crohn'sdisease, rheumatoid arthritis, diabetes, cataract formation, uvetis,emphysema, gastric ulcers, oxygen toxicity, neoplasia, undesired cellapoptosis, radiation sickness.
 25. The systemic administration of apharmaceutically effective amount of the composition according to claim1 to a mammal, to promote the natural production of glutathione in thebiologically active cells of the mammal which accelerates thedetoxification of ethanol and alleviates symptoms associated withexcessive ethanol imbibation.
 26. The composition of claim 1 furthercomprising a probiotic, said probiotic for promoting the breakdown andabsorption of nutrients, the elimination of toxins and to inhibit thegrowth of harmful bacteria in the gastrointestinal tract, therebyfacilitating the absorption of N-acetylcysteine into thegastrointestinal tract.
 27. The probiotic of claim 1, wherein saidprobiotic is a composition of “healthy bacteria” containing one or moreof said healthy bacteria selected from the group comprisingbifidobacterium longum, bifidobacterium infantis, lactobacillusacidophilus, lactobacillus casei, lactobacillus rhamnosus, saccharomycesboulardi, propionibacteria and enterococci.
 28. The composition of claim2 further comprising 1-glutamine, said component being an essentialdietary component to promote the support of gastrointestinal growth andfunction, thus facilitating the absorption of N-acetylcysteine throughthe gastrointestinal tract.
 29. The composition of claim 4 whereinN-acetyl-d-glucosamine promotes the biosynthesis of mucosalglycoproteins which make up the glycocalyx, a layer of the gut mucosawhich acts to protect the tissue of the gastrointestinal tract whileproviding a selectively absorptive surface, thus facilitating theabsorption of N-acetylcysteine into the gastrointestinal tracts.
 30. Acomposition of matter which comprises in admixture: N-acetylcysteine,N-acetyl-d-glucosamine, vitamin C, present in an amount by weight of 1to 20 parts N-acetylcysteine, 0.5 to 2 parts N-acetyl-d-glucosamine and5 to 50 parts vitamin C; whereby the amount of vitamin C is in an amountof at least 1000 mg or greater to facilitate the absorption ofN-acetylcysteine across a cellular membrane; and a pharmaceuticallyacceptable carrier for oral administration.
 31. A composition of matterwhich comprises in admixture: 3 parts N-acetylcysteine, 1 partN-acetyl-d-glucosamine and 2 parts vitamin C; whereby the amount ofvitamin C is in an amount of at least 1000 mg or greater to facilitatethe absorption of N-acetylcysteine across the cellular membrane; and apharmaceutically acceptable carrier for oral administration.
 32. Acomposition of matter of claim 30, which comprises in admixture; furthercomprising one or more substances selected from the group consisting ofalpha-lipoic acid, sylmarin, quercitin, L-glutamine, a probiotic, anddietary protein.
 33. The composition of claim 31, further comprisingalpha-lipoic acid, sylmarin, quercitin, L-glutamine, and a probiotic.34. The composition of claim 33, further comprising dietary protein. 35.The composition of claim 30, further comprising flavorants.
 36. A methodof stimulating natural production of glutathione in cells of a mammalwhich comprises systemic administration of a pharmaceutically effectiveamount of a composition of claim
 30. 37. The method of claim 36, whereinthe mammal is suffering from hepatitis.
 38. The method of claim 36,wherein the mammal is suffering from HIV.
 39. A method of stimulatingnatural production of glutathione in cells of the mammal and to promoteshift of T-cell balance from TH2 to TH1 and decrease levels of IgE whichcomprises systemic administration of a pharmaceutically effective amountof a composition of claim 32 .
 40. A method of decreasing serumcholesterol and triglycerides in a mammal which comprises systemicadministration of a pharmaceutically effective amount of a compositionof claim
 32. 41. A method of improving immune defense productions andthereby mitigating progression of illnesses to thereby limit fatigue toa mammal suffering from one or more of the following illnesses selectedfrom the group consisting of chronic viral infections: HIV, hepatitis C,chronic fatigue, immuno deficiency syndrome, immune deficiencies,cancer, B-cell malignancies, lymphomas, chronic leukemia, myelomaWaldenstrom's and MGUS, which comprises systemic administration of apharmaceutically effective amount of the composition according to claim32 to a mammal.
 42. The method of decreasing fatigue in a mammal whichcomprises systemic administration of the composition of claim 32 to amammal.
 43. A method of decreasing the biological effects of stresswhich comprises systemic administration of a pharmaceutically effectiveamount of the composition according to claim 32 to a mammal.
 44. Amethod of increasing energy and improving physical performance whichcomprises systemic administration of a pharmaceutically effective amountof the composition according to claim 32 to a mammal.
 45. The method ofclaim 36, wherein the pharmaceutically effective amount is 0.1 mg/kg toabout 50 mg/kg of body weight of the mammal, daily.
 46. The method ofclaim 36, wherein the pharmaceutically effective amount is 0.5 mg/kg toabout 25 mg/kg of body weight of the mammal, daily.
 47. The method ofclaim 36, wherein the composition further comprising one or more of thefollowing substances selected from the group consisting of alpha-lipoicacid, sylmarin, quercitin, L-glutamine, a probiotic, and dietaryprotein.
 48. The method of claim 47, wherein the composition furthercomprising one or more of the following substances selected from thegroup consisting of alpha-lipoic acid, sylmarin, quercitin, L-glutamine,and a probiotic.
 49. A method of stimulating the natural production ofglutathione in the cells of the mammal and reduce symptoms of diseasescaused by excess unneutralized free radicals which comprises thesystemic administration of a pharmaceutically effective amount of thecomposition of claim
 32. 50. The method of claim 49, wherein thecomposition further comprising one or more of the following substancesselected from the group consisting of alpha-lipoic acid, sylmarin,quercitin, L-glutamine, a probiotic, and dietary protein.
 51. The methodof claim 50, wherein the composition further comprising one or more ofthe following substances selected from the group consisting ofalpha-lipoic acid, sylmarin, quercitin, L-glutamine, and a probiotic.52. The method of claim 49, wherein the disease is selected from thegroup consisting of pulmonary oxygen toxicity, adult respiratorydistress syndrome, bronchopulmonery dysplasia, sepsis syndrome,Parkinson's disease, encephalitis, endotoxemia, anoxia induced neuronaldamage, ischemic reperfusion injury, inflammatory diseases, systemiclupus erythematosis, myocardial infarction, stroke, traumatichemorrhage, spinal cord trauma, Crohn's disease, rheumatoid arthritis,diabetes, cataract formation, uvetis, emphysema, gastric ulcers, oxygentoxicity, neoplasia, undesired cell apoptosis, and radiation sickness.53. The method of claim 50, wherein the disease is selected from thegroup consisting of pulmonary oxygen toxicity, adult respiratorydistress syndrome, bronchopulmonery dysplasia, sepsis syndrome,Parkinson's disease, encephalitis, endotoxemia, anoxia induced neuronaldamage, ischemic reperfusion injury, inflammatory diseases, systemiclupus erythematosis, myocardial infarction, stroke, traumatichemorrhage, spinal cord trauma, Crohn's disease, rheumatoid arthritis,diabetes, cataract formation, uvetis, emphysema, gastric ulcers, oxygentoxicity, neoplasia, undesired cell apoptosis, and radiation sickness.54. The method of claim 51, wherein the disease is selected from thegroup consisting of pulmonary oxygen toxicity, adult respiratorydistress syndrome, bronchopulmonery dysplasia, sepsis syndrome,Parkinson's disease, encephalitis, endotoxemia, anoxia induced neuronaldamage, ischemic reperfusion injury, inflammatory diseases, systemiclupus erythematosis, myocardial infarction, stroke, traumatichemorrhage, spinal cord trauma, Crohn's disease, rheumatoid arthritis,diabetes, cataract formation, uvetis, emphysema, gastric ulcers, oxygentoxicity, neoplasia, undesired cell apoptosis, and radiation sickness.55. The method of claim 36, wherein the method of stimulating naturalproduction of glutathione in cells of a mammal results in detoxificationof ethanol and alleviation of symptoms associated with excessive ethanolimbibation.
 56. The composition of claim 32 wherein the one or moresubstances is L-glutamine.